In January, a panel of researchers released newly updated Department of Health and Human Service (DHHS) Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents; the initial guidelines were published in 1998.
Among the features of the updated guidelines are a discussion of the goals of anti-HIV treatment, use of resistance testing, and adherence issues; an emphasis on individualized therapy; and expanded information on metabolic side effects. According to the panel that prepared the guidelines, "Physicians and patients must weigh the risks and benefits of starting antiretroviral therapy and make individualized and informed decisions." The revised recommendations state that various factors should be taken into account when considering optimal therapy for those with early HIV infection, including pill burden, dosing frequency, toxicity, and other considerations, not simply the ability to suppress viral load.
Also in January, the DHHS published an updated version of the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, which includes new information on the use of amprenavir (Agenerase) in children. The Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant Women Infected with HIV-1 for Maternal Health and for Reducing Perinatal HIV-1 Transmission in the United States were also updated.
The latest versions of all the guidelines are available at www.hivatis.org, or by calling 800-448-0440.
In late February, the U.S. Food and Drug Administration (FDA) granted full approval to efavirenz, manufactured by DuPont Pharmaceuticals; the drug was previously available under an accelerated approval protocol.
Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that can be taken once a day as part of a combination regimen with other anti-HIV drugs. The approval of efavirenz was based on data concerning the long-term efficacy of the drug. Efavirenz has become the most widely sold anti-HIV drug -- surpassing indinavir (Crixivan), the most popular protease inhibitor (PI) -- and is increasingly being used in protease-sparing regimens.
The FDA also recently approved 1,250mg twice-daily dosing of the PI nelfinavir. Interim results of a Phase III clinical trial indicate that this dose is as effective as the previous standard dose of 750mg three times per day; the incidence of side effects with the twice-daily and three-times-daily doses were similar.
In January, Glaxo Wellcome sent a letter to health-care providers alerting them to new symptoms that may indicate an abacavir hypersensitivity reaction.
In earlier studies, such a reaction was seen in 3-5% of people taking the drug, and was characterized by flu-like symptoms such as nausea, vomiting, abdominal pain, fever, fatigue, or muscle aches; a skin rash may also occur. Now, the drug's manufacturer reports that symptoms more akin to those of a common cold -- sore throat, cough, and shortness of breath -- may also signal a reaction to abacavir.
Glaxo Wellcome stated that approximately 20% of people who have experienced a hypersensitivity reaction to abacavir, and 80% (9) of the 11 persons worldwide who have died as a result, experienced the latter symptoms. Restarting abacavir after a hypersensitivity reaction may be life threatening. People who experience any of these symptoms when taking abacavir should contact their physician or an emergency room immediately; once they stop taking abacavir, they should not restart the drug.
Results of three studies were published in the February 12, 2000 issue of the Lancet showing that St. John's wort, an herbal supplement used to treat depression and anxiety, can interact dangerously with various drugs.
One study, conducted by researchers at the National Institutes of Health (NIH), showed that simultaneous use of St. John's wort could cause blood levels of the PI indinavir to drop dramatically (an average of 57%), potentially leading to failure of viral suppression or the development of drug resistance.
The second study, conducted by researchers at University Hospital in Zurich, Switzerland, showed that the herb interacts with cyclosporine (Neoral), an anti-inflammatory drug used by organ transplant recipients to lessen the chance that the body will reject the new organ; this interaction led to heart transplant rejections in two persons.
Finally, researchers showed that St. John's wort interacts with warfarin (Coumadin), a drug used to reduce blood clotting. The interactions occur because St. John's wort is metabolized by the same CP450 liver enzyme system that metabolizes many drugs. The recent reports have led to calls for increased regulation of herbs and supplements.
It has long been known that anti-HIV drugs can put a strain on the liver. New research suggests that serious liver damage is more common that previously thought in people taking ritonavir.
In the January 5, 2000 issue of the Journal of the American Medical Association, Mark Sulkowski, M.D., and colleagues from Johns Hopkins University in Baltimore reported that after six months of various highly active antiretroviral therapy (HAART) regimens, approximately 10% of people in their study experienced liver damage severe enough to warrant stopping anti-HIV therapy; half of these cases occurred in people taking ritonavir. Once the drug was discontinued, none of the participants suffered permanent liver damage. Lower rates of liver toxicity were seen in people taking nelfinavir, indinavir, and dual nucleoside analog (NRTI) regimens.Overall, liver toxicity was five times more common in people taking ritonavir than in those taking the other drugs. Just over half the participants who received a PI-containing regimen had chronic hepatitis B or C in addition to HIV.
Despite the danger, the authors concluded that for most people -- including those coinfected with hepatitis B or C -- the benefits of PI therapy outweigh the risks. However, Sulkowsi noted, "If you have a choice, it may be prudent in a patient with hepatitis C to avoid using ritonavir if you can." Physicians should regularly monitor liver enzyme levels of their patients taking HAART.
This past November, Ronald Gray, M.D., and colleagues from Johns Hopkins University reported study results indicating that urine tests for HIV antibodies appear to be as sensitive and accurate as standard blood antibody tests.
The study involved over 200 adults in Uganda who received both urine and blood tests during a single clinic visit. The tests appear to work well with both fresh and stored (refrigerated) urine. The researchers said that the urine test may prove more popular than blood tests because many people seek to avoid needles, and the test may be safer due to the reduction of the risk of needlestick accidents.
In March, David Bangsberg, M.D., and colleagues from the University of California at San Francisco (UCSF) reported that low-income urban residents are capable of adhering closely to antiretroviral regimens that contain a PI.
The 34 study participants were homeless or lived in single-room-occupancy hotels in San Francisco; the population had high rates of mental illness, drug use, and incarceration. The researchers determined adherence rates by using participant self-reports, randomly scheduled pill counts, and electronic monitors in pill bottles. Adherence was monitored for up to ten weeks.
Many patient advocates have expressed concern that indigent persons might have trouble adhering to HAART regimens that require numerous daily pills and changes in eating schedules. Instead, Dr. Bangsberg's team found that 35% of study participants achieved over 90% adherence. The researchers noted that the three adherence measures used gave similar results. The study was published in the March issue of AIDS.
Adherence continues to be a major contributor to the success of anti-HIV therapy. Dr. Bangsberg and colleagues found that a 10% decrease in adherence was associated with a doubling of HIV viral load. According to UCSF's Andrew Moss, M.D., "Near-perfect adherence is essential to achieve undetectable levels of viral replication."
Jonathan Angel, M.D., of Ottawa Hospital in Canada presented at the 7th Conference on Retroviruses and Opportunistic Infections (CROI) one of the first reported cases of probable "superinfection" with a different strain of HIV.
The case study involved a 40-year-old HIV positive gay man who had remained symptom-free for eight years. In 1997, he became ill, experienced an increase in viral load and a decrease in CD4 cell count, and did not respond to new anti-HIV therapies. The man reported that he had recently begun a new relationship with a partner who had extensive experience with antiretroviral drugs and had developed drug-resistant virus. The first man's HIV was originally distinct from that of his partner, but later became similar to the partner's resistant strain.
Although researchers have long suspected that HIV reinfection is possible -- and it has been demonstrated in chimpanzees -- this case provides the "strongest evidence yet" that superinfection occurs, according to Dr. Angel.
Mitchell Katz, M.D., of the San Francisco Department of Public Health and colleagues from UCSF reported in February that none of the individuals who received postexposure prophylaxis (PEP) following risky sex or drug use have become infected with HIV.
The observational study involved over 400 people who received a month-long course of antiretroviral therapy following their suspected exposure; most of the potential exposures involved unprotected sex, primarily anal and vaginal intercourse. Seventy-eight percent of participants successfully completed the full course of treatment.
It is not possible to estimate the effectiveness of PEP, however, because it is impossible to know which of the participants might have become infected without the so-called morning-after treatment.
Researchers from the Centers for Disease Control and Prevention (CDC) and UCSF reported in February that oral sex on men appears to be a more frequent method of HIV transmission than previously believed.
In a study of 102 newly infected gay and bisexual men in San Francisco, unprotected receptive oral sex was identified as the probable cause of transmission for 8% of the men. To determine the method of infection, researchers used the new detuned ELISA test, which can help pinpoint the time of infection, along with medical records and interviews with the men and their partners.According to Frederick Hecht, M.D., of UCSF, "There's a lot less unprotected anal sex than there was a few years ago, [but] there hasn't been the same reduction in unprotected oral sex, which has probably become an important mode of transmission."
Still, Dr. Hecht noted that unprotected receptive anal sex is probably 100 times more likely than oral sex to transmit HIV. The CDC's Helene Gayle said that if oral sex alone played a large role in the spread of AIDS, this would already have become obvious during the past 20 years. Although details about the men's oral health was not included on the poster presented at the 7th CROI, Dr. Hecht examined his data at the request of the Washington Blade newspaper and found that four of the eight infected men had gum disease or oral ulcers, factors that are known to facilitate the entry of the virus.
In the March 1, 2000 issue of the Journal of the American Medical Association, researchers reported that infants who were formula-fed had lower rates of HIV infection than breast-fed infants.
The study included over 400 HIV positive women in Nairobi, Kenya, half of whom breast-fed their newborns and half of whom fed babies infant formula. Of the 401 infants in the study, 61 of the breast-fed babies became infected with HIV compared with 31 of the formula-fed babies. Despite this difference, mortality rates for the two groups of infants were similar at two years of age. The study showed that HIV was most likely to be transmitted during the first six months of life, during which time 75% of transmissions occurred.
The authors estimate that formula-feeding may reduce perinatal HIV transmission by more than 40% compared with breast-feeding; however, they noted that poverty, lack of clean water, and other socioeconomic and cultural factors may make formula-feeding difficult or impossible for many women. [Ed. note: Previous studies of breast- vs. formula-feeding have been complicated by the fact that a significant number of participants mixed the two modes; e.g., some women in the formula-feeding group reported occasionally breast-feeding during the night.]
A study published in the December issue of Nature Medicine suggests that HIV infects men and women differently.
Julie Overbaugh, M.D., and colleagues from the Fred Hutchinson Cancer Research Center in Seattle, WA, found that women tend to be infected with multiple strains of HIV at once, while men are usually initially infected with a single strain. Study participants were female prostitutes and male truck drivers in Kenya. Of the 32 women, 20 were initially infected with multiple HIV strains, although they had been infected by a single sexual partner; the ten men in the study were initially infected with a single HIV strain.
The results suggest that HIV may infect different cell types or may replicate differently in women, and that it may be more difficult to develop a vaccine that is effective in women.
At the 7th CROI, Preston Marx, M.D., and colleagues from the Aaron Diamond AIDS Research Center in New York presented study results showing that estrogen protected female monkeys from vaginal infection with simian immunodeficiency virus (SIV), a virus similar to HIV.
The monkeys in the study, which had their ovaries removed and thus produced no natural estrogen or progesterone, were given estrogen, progesterone, or no hormones. Monkeys that received estrogen injections developed a thicker layer of cells lining the vagina, which appeared to protect them from infection. Monkeys injected with progesterone, which tends to thin the vaginal lining, were infected at rates similar to monkeys that received no hormones.
The research may lead to the development of an estrogen cream that could help protect women against HIV infection.
Six Kenyan women have developed HIV infection after remaining uninfected for several years, constituting a setback for HIV vaccine research.
The women were part of a group of 43 Kenyan prostitutes who researchers had suggested were immune to HIV because they had experienced multiple exposures to the virus over the course of 15 years without becoming infected. The findings were reported in late January by researchers from Oxford University. Because the women had high numbers of cytotoxic T-lymphocytes (CTLs), which destroy HIV-infected cells, scientists had hoped the women could provide clues on how to induce a potent anti-HIV immune response using a vaccine. Such a vaccine seemed effective in monkeys, and was slated to begin Phase I clinical, and was slated to begin Phase I clinical trials this year.
However, the women, now retired from sex work, appear to have lost their immunity. The new findings suggest that a vaccine will have to be administered repeatedly to maintain a durable (effective) immune response.
A review article by Beatrice Hahn, M.D., of the University of Alabama at Birmingham in the January 28 issue of Science suggests that HIV originated in western equatorial Africa in 1930, two decades earlier than previously believed.
The research discussed in the article was conducted by a team from Northwestern University, the University of Alabama, and Los Alamos National Laboratory. The new estimates are based on supercomputer models of HIV evolution derived from a large database of HIV samples at Los Alamos National Laboratory; genetic sequences were used to construct an evolutionary tree for the virus.
Anthropological evidence lends credence to the new date. Early in the twentieth century, changes related to colonialism, forced labor on a railroad, and village dislocation could have set the stage for the transmission of the virus. Bruce Fetter, a social historian from the University of Wisconsin, suggested that malnourished railroad workers might have resorted to killing chimpanzees for food, which could have led to bites and injuries that allowed the virus to pass from chimps to humans.
The first known case of HIV was detected in a plasma sample stored in 1959 in Kinshasa, Zaire, near the terminus of the Congo-Ocean railroad. Colonizers also instituted widespread vaccination programs in which needles were used on multiple people. Finally, in the early decades of the century chimpanzees began to be captured for zoos and circuses. Any of these factors could have contributed to the cross-species jump and subsequent spread of HIV among humans.
Liz Highleyman is a freelance medical writer.
Back to the SFAF BETA Spring, 2000 contents page.